Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus.
OBJECTIVE
Gene identification in small families segregating autosomal dominant sensorineural hearing loss presents a significant challenge. To address this challenge, we have developed a machine learning-based software tool, AudioGene v2.0, to prioritize candidate genes for mutation screening based on audioprofiling.


METHODS
We analyzed audiometric data from a cohort of American families with high-frequency autosomal dominant sensorineural hearing loss. Those families predicted to have a DFNA2 audioprofile by AudioGene v2.0 were screened for mutations in the KCNQ4 gene.


RESULTS
Two novel missense mutations and a stop mutation were detected in three American families predicted to have DFNA2-related deafness for a positive predictive value of 6.3%. The false negative rate was 0%. The missense mutations were located in the channel pore region and the stop mutation was in transmembrane domain S5. The latter is the first DFNA2-causing stop mutation reported in KCNQ4.


CONCLUSIONS
Our data suggest that the N-terminal end of the P-loop is crucial in maintaining the integrity of the KCNQ4 channel pore and AudioGene audioprofile analysis can effectively prioritize genes for mutation screening in small families segregating high-frequency autosomal dominant sensorineural hearing loss. AudioGene software will be made freely available to clinicians and researchers once it has been fully validated.
Hildebrand
Michael S
MS
Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA. michael-hildebrand@uiowa.edu
Tack
Dylan
D
McMordie
Sarah J
SJ
DeLuca
Adam
A
Hur
In Ae
IA
Nishimura
Carla
C
Huygen
Patrick
P
Casavant
Thomas L
TL
Smith
Richard J H
RJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005190:Family; D005799:Genes, Dominant; D034381:Hearing Loss / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006320:Hearing Tests; D006801:Humans; D051656:KCNQ Potassium Channels / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D012984:Software
D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human